Acute infection with HCV leads to chronic infection or spontaneous clearance, making it a model chronic infection. In the previous grant cycle, we have made important contributions to defining the defects in host innate and adaptive immunity that contribute to the remarkable predilection to chronicity of HCV infection. We and others have established that a polymorphism near the IL28B (1FNA.3) gene is profoundly associated with spontaneous HCV clearance. However, until recently, studies of the predominant SNPs failed to uncover a functional polymorphism. Recently, a dinucleotide polymorphism upstream of IFNA,3 was found to create (AG) or disrupt (TT) an open reading frame in a new locus, 1FNA.4. The finding that the unfavorable allele is associated with production of 1FNX,4 raises the distinct possibility that IFNA,4 production in response to viral infection has undesirable consequences for chronicity, including chronic stimulation of ISGs. In contrast, another study found that PBMCs from patients harboring the unfavorable AG exhibited lower poly(l:C)-induced IFNXS and IP-10 expression than those harboring TT. The exciting finding of a functional polymorphism now enables the mechanistic dissection of the effect of genotype on IFN and ISG Induction in both hepatocytes and PBMCs. Recent data from mouse models of LCMV have shown that type I IFN released during chronic infection induces ISGs that through suppressive cytokines, contribute to virusspecific T cell hypofunction. Strikingly, blockade of type I IFN signaling during the chronic phase restores T cell function and produces a paradoxical antiviral effect. These findings can now be readily tested in the paradigm human chronic infection model, HCV. We will therefore test the overall hypothesis that HCV associated type I IFN signaling exerts a long term Immune suppressive effect that can be partially to completely reversed by removing virus. With new direct acting antiviral (DAA) combinations promising high viral cure rates and independence IFN treatment, we now have the unprecedented opportunity to evaluate the effect of DAA-mediated cure on recovery of these impaired functions. Project 1 Aims: (1). Characterize alterations in the type I ISG response, cytokine and APC environment during DAA-mediated viral cure; (2) Evaluate the contribution of a functional SNP near the IFN Lamda3/IFN Lamda4 locus to chronic HCV and to immune recovery with DAA-mediated viral cure (genotype-phenotype correlation). We will use a unique cohort of patients undergoing DAA therapy and comprehensively collect immune samples to support these Aims.